This invention pertains to a process for the production of substituted cyclopropane derivatives.
Cyclopropane derivatives are compounds having important known and potential commercial applications. They are useful, for example, as insecticides, as ingredients of cosmetics, as pharmaceuticals, and in particular as tranquilizers. In addition, they are useful intermediates for the procedures of the synthetic organic chemical industry.
As is well known, substituted cyclopropanes are difficult of preparation. The prior art methods for their production have required two or more reactions using as starting materials compounds which themselves often are difficult of preparation. Yields have been correspondingly low.
Certain 1,1,2 substituted cyclopropane derivatives have been prepared heretofor using trimethylsulfoxonium iodide. In a procedure described by E. J. Corey and M. Chaykovsky, J. Amer. Chem. Soc., 87, 1353 (1965), trimethylsulfoxonium iodide was treated with sodium hydride to form dimethylsulfoxonium methylide and this reagent was reacted with alpha, beta-unsaturated ketone derivatives to form substituted cyclopropanes. Following this report, other investigators i.e. C. Kaiser, et al, J. Org. Chem. 30, 3972 (1965) and S. R. Landor and N. Punja, J. Chem. Soc. 2495 (1967), prepared 1,1,2 substituted cyclopropane derivatives by reacting dimethylsulfoxonium methylide with alpha, beta-unsaturated carboxylic acid derivatives.
Frequently, for use in the latter procedure the required alpha, beta-unsaturated carboxylic derivative is not readily available and must be prepared as a starting material. For this starting material, the involved reaction is often a condensation of the appropriate aldehyde and active methylene compound, followed by the isolation and the purification of the desired product.
The present invention is predicated on the discovery that a wide variety of cyclopropane products substituted in the 1, 2 and 3 positions may be produced in practical yields in reaction times in the order of one hour, or even less, and in a single reaction vessel by the interreaction of an aldehyde, an active methylene compound, a sulfoxonium or sulfonium bromide or iodide and a strong base, all dissolved in a reaction-inert organic solvent. The reaction product is a cyclopropane substituted in positions corresponding to the particular reagents employed.
The reaction takes place according to the following exemplary general equation, using trimethyl sulfoxonium iodide (where R.sup.4 .dbd. H) and sodium hydride as an exemplary strong base: ##STR1##
Without commitment to any particular theory, the mechanism for the above reaction is novel in that the reaction leads directly to the production of the substituted cyclopropane product. In particular, it is novel in that it does not involve the in situ formation of an intermediate alpha, beta-unsaturated carboxylic acid derivative.
As is well known, the conditions for the preparation of alpha, beta-unsaturated carboxylic acid derivatives generally require high temperature and longer reaction times than are used in the present invention (G. Jones, Organic Reactions, Vol. 15 p. 331-4 (1967). Furthermore, tests carried out by me using gas chromatography have failed to reveal the presence of any alpha, beta-unsaturated carboxylic acid derivatives in the substituted cyclopropane-yielding reaction mixtures employed in executing the process of my invention.
In addition, the reaction mechanism does not involve the formation of an intermediate epoxide derivative. While it is established, E. J. Corey and M. Chaykovsky, J. American Chemical Society 87, 1353 (1965), that aldehydes and dimethylsulfoxonium methylide react to form epoxides, it is further established, J. Org. Chem. 29, 2810 (1964), and also Bavin et al, J. Chemical Society 1964 p. 4535, that the addition of an active methylene compound to an epoxide does not produce cyclopropane derivatives. Accordingly, in the light of present knowledge, the hereindescribed reaction is totally new and does not follow the mechanism of any other reaction known to produce cyclopropane derivatives.
The procedure of my invention has many significant advantages.
It is a simple, one-step procedure. It is carried out in a very short reaction time. Readily available starting materials may be used in many instances. The reaction may be carried out in simple equipment at low temperatures. Super atmospheric pressures and the use of catalysts are not required. Practical yields of products are obtained. The procedure is versatile in that it may be directed to the production of a wide variety of cyclopropane derivatives substituted in the 1, 2 and 3 positions with selective constituent groups.